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138 Cards in this Set

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  • Back
Which components of LADME are associated with PO only?
Liberation and Absorption
Non-linear kinetics involves _______________ systems.
Saturable
What is the unit for F?
There is none
Moxifloxacin IV bioavailable fraction?
1
Formula for F for oral formulation?
F = ffp x fa
ffp means?
Fraction escaping 1st pass
fa means?
Fraction absorbed
Relationship of CL to T1/2
Inverse
Unit of CL
L/hr
Normal Hepatic Blood Flow
90 L/hr
A drug with a CL of 88 and HBF of 90 would be called what?
A high E (efficiency drug)
Why is IBW used when calculating CL?
Because obesity does not affect the size of the clearing organ
IBW formula for men
50kg + 2.3kg per inch over 60
IBW formula for women
45.5kg + 2.3 kg per inch over 60
Does Vd affect CL?
Yes
Does T1/2 affect Vd?
No
After how many T1/2s are most drugs considered to be effectively gone?
5
What does a zero input mean when administering a drug?
The drug is administered as a continuous infusion
What is Emax?
The maximumal pharmacodynamic response
T / F Emax only occurs when all receptors are occupied?
False
Emax CAN occur if all receptors are occupied, but doesn't have to
Describe the Fixed Effect PD model
1 or 0 - present or not
Threshold can very
What is the EC50 in terms of the sigmoid Emax model?
The effective concentration producing half maximal effect
In terms of the Sigmoid Emax model, what does E0 mean?
It is the background effect factor that shifts the curve upwards
Describe the logarithmic PD model
Linearizes the sigmoid max model when looking at the 20-80% Emax, limited. Allows for comparison of potency/competetive model
Describe the Linear model
E = S x C
S = Slope parameter
Fucking useless, move on
Describe the Sensitization model for PD
Higher on the way down since the receptor is now horny.

Its in a counterclockwise graph
Describe the tolerance model
Lower on the way down, receptors begin to ignore (afrin)

Clockwise graph
In a single compartmental model, is increasing the dose an efficent way to increase effect?
No - The Y-axis is in logarithmic form and time is in linear, so giving a 2nd dose at a later time such as when there is loss of effect will give a greater/longer effect
Describe what influences duration of effect in a multicompartmental model
Depends on distribution and depth (amt of drug present and rate of input/output).

Is not a function of dose.
Describe the effect of giving the same total dose over shorter intervals on AUC and Css
AUC will increase.

Css will remain the same
________ drug is available for effect and clearance typically.
Unbound
Why can total drug concentration be used for dose adjustment (although total drug will not necessarily be causing the effect)
It is typically proportional to the unbound fraction, which is available for effect and clearance.
Where is albumin made?
Liver
What is the Alb half life?
19 days
Where is Albumin predominately found? Extra/intra vascular?
Extravascular
What types of drugs does albumin bind?
Acidic and neutral mostly
What are the two binding sites of albumin?
Warfarin and indole-bzd
What can cause alb to have a confirmational change and displace other drugs?
Bilirubin
Sulfonamides, binding site
Warfarin ALB
Alb binding site: Sulfonamides
Warfarin
Alb binding site: Phenytoin
Warfarin
Alb binding site: VPA
Warfarin - very pushy
Alb binding site: NSAIDs
Both
Alb binding site: Semisynthetic PCNs
Indole bzd
Alb binding site: Probenicid
Indole-bzd
Alb binding site: Medium chain FA
Indole - bzd
AAG binds what types of drugs
Basic/neutral
Which binding protein is considered "Acute phase reactive"
AAG
What can affect AAG production?
Stress mediated by cytokines
T1/2 of AAG
5 days (short)
AAG is predominantely:
A: Extravascular
B: Intravascular
B
Liver Dz, effect on Albumin
Decrease
Lipoproteins bind what types of drugs?
Basic / neutral
Describe saturation of Lipoproteins
Many drugs Cannot be saturated since partitioned into core
Which drugs are partitioned into the core of lipoproteins?
Cyclo, probucol, dig, sirolimus, pindolol
Cyclosporin Binding (binding lecture)
Lipoprotein core
Dig binding (binding lecture)
Lipoprotein core
Sirolimus Binding
Lipopreotein core
TCA binding
Protein component of lipoprotein, saturable
Quinidine binding
Protein component of lipoprotein, saturable
Which drugs bind to the protein component of lipoprotein (saturable component)
TCAs / Quinidine
Describe altered drug binding in: Neonates
-Alb
-AAG
+Bili/FFAs
Describe altered drug binding in: Elderly
- Alb
Glycosylation of Alb/AAG (altered affinity)
Describe altered drug binding in: Pregnancy
-Alb
+FFA
-AAG
Which drugs will have a higher fu in pregnancy?
Salicylates
Phenytoin
Valium
VPA
Describe normalization of proteins after delivery of a baby (small human)
AAG/FFA in a few days, Alb in a month
Describe altered drug binding in: Obesity
No effect
Describe altered drug binding in: Smoking
No effect
Describe altered drug binding in: Diurnal
AAG/FFAs (Lipoproteins) due to food/cytokines
Describe altered drug binding in: Nephrotic syndrome
-Alb
+AAG
Describe altered drug binding in: Uremia
Drug displacement/confirmational changes
+AAG
Describe what drugs would have major changes in protein binding in uremia or nephrotic syndrome
Phenytoin
MPA
Fibrates
WILL ALL +fu
Describe altered drug binding in: Trauma
+AAG
-Alb
Describe altered drug binding in: OCP use
-AAG
Increase lido/valium levels
Phenytoin population value for Vm
Vm = 7
Phenytoin population value for Km
5
Initial dose equation for phenytoin
Below equals dose
(Vm x Cp)
------------
Km + Cp
How do you calculate Vm for phenytoin once a lab value is known?
Below equals Vm

Km x Dose
---------- + Dose
Css
Phenytoin

What is Km
[] at which rate of metabolism is 1/2 the max rate, Vm
Phenytoin, what is Vm
The maximum rate of metabolism
Phenytoin

If C <<< Km, what happens?
1st order
Vm x Cp Vm x Cp
--------- => --------
Km + Cp Km

(Km + Cp) ==> Km
At low doses, Phenytoin follows _____ order kinetics
1st order
At high doses,phenytoin follows _____ order kinetics
Zero
Ideal therapeutic range for Phenytoin
10-20
Phenytoin metabolism in peds
Faster
Phenytoin metabolism in old people
Slower, no one cares though
How long does phenytoin take to reach Css?
2 weeks, unless Km is lower
Phenytoin is a substrate of what enzyme?
CYP 2C9
What happens if Albumin tanks to phenytoin?
+fu --> + effects (lower dose) AND + CL (lower total level)
What would be the effect on Vmax of co-administration of phenytoin with CBZ or phenobarbital?
Increased due to induction
What would be the effect on Vmax of Cirrhosis for phenytoin?
Decreased
What would be the effect of competitive inhibition on Km for Phenytoin?
Increased, need more drug to overcome inhibition
What would be the effect of decreased albumin on Km for phenytoin?
Lower (More available to be chewed up)
Effect of renal dysfunction on Phenytoin
+/- preotein and lft effects
What would be the effect of microalbuminuria on phenytoin levels?
- Alb
- Total level
+ Fu
Dose related ADRs of Phenytoin
Drowsiness
Confusion
Nystagmus
Ataxia
Slurred speech
Nausea
Unusual behavior
MS changes
Coma
Non dose related ADRs of Phenytoin
Hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, SJS

For these, must change drug
CBZ Therapeutic range
4-12
Autoinduction of CBZ occurs during which period?
21-28 days
At steady state, what is the T1/2 of CBZ?
12 h
Describe CBZ levels upon initiation and as times progress
Levels will be higher earlier on
CBZ + Food = ?
Increased absorption with IR --> Toxicity risk
With what doses is CBZ linear?
600-1400
At what doses of IR is CBZ not absorbed well?
>20mg/kg
Dosing frequency of CBZ ER
BID
CBZ Protein binding
Highly variable
Metabolism of CBZ
99% hepatic, no renal
What happens if CBZ is administered with other antiepileptics?
-T1/2 due to 3A4, thus avoid
VPA absorption
Well absorbed
VPA: Effect of EC on PK paramaeters
Delayed absorption, but no change in extent
Describe VPA bioequivalence between formulations
ER not bioequivalent, must increase dose 10-20%
For what Antiepileptic agent does CSF predict serum concentration?
VPA
Gabapentin Elimination
Renal excretion
Which Anti-epileptic is the only one that is renally cleared?
Gabapentin
Describe entry into CNS of Gabapentin
Active transport
Descibe absorption and entry into CNS mechanism for Gabapentin
active transporter, thus limited
Describe utility of blood levels for gabapentin
Nuttin
Which Anti-epileptic drug is affected by L-amino acid transporters?
Gabapentin
CKD
Chronic Kidney Disease
3 things CKD can affect
Distribution
Protein Binding
Bioavailability
CLr is a composite of what 3 components
Glomerular filtration(passive)
Tubular Secretion(Active)
Tubular reabsorption(Active)
What agent is ideal for determining Renal Fx
Inulin
What relationship exists between SCr and GFR?
Inverse
Utilization of Creatinine to determine kidney function depends on what assumptions?
1. Constant Cr production
2. Cr is from muscle and constant
3. Cr is filtered only
4. Accurate measurement
5. Urine collection is complete
What agent competes for creatinine secretion?
Cimetidine
What agent competes for anionic pump (PCN) secretion?
Probenecid
Active secretion method
Carrier mediated (pumps) - Competitive
What can be filtered by glomerular filtration?
Free drug
Mechanisms of renal reabsorption
1. Active transport
2. Passive back diffusion
3. Endocytosis
How can CKD affect Vd?
Fluid overload
Altered protein binding
Protein binding effects caused by end stage renal failure
-Alb
+AAG
Which type of renal failure has more effect on the liver?
(In terms of protein expression)
Chronic Renal failure
(Protein expression)
3 types of Dialysis
1. Hemodialysis
2. Peritoneal Dialysis
3. Continuous renal replacement therapies
Drugs that are highly protein bound are ________ likely to be dialyzed
Less
A drug with a large Vd is _____ likely to be cleared by dialysis.
Less
How long do you wait before drawing blood levels after dialysis?
2 hours, allow for redistribution
Why would you still give a loading dose in a hemodialysis patient for a drug that is poorly removed by dialysis?
The drug must still fill the Vd, its maintenance doses that must be adjusted
What is the dosage adjustment factor formula?
Q = 1 - [Fe (1-KF)]
fe = Fraction eliminatd unchanged
KF = CrCL / 120